RU2734417C2 - Fizzy compositions based on ornithine aspartate - Google Patents

Abstract

FIELD: pharmaceutical industry.

SUBSTANCE: group of inventions relates to a method for making fizzy composition based on ornithine aspartate, according to which is granulated mixture containing ornithine aspartate and gas-forming component, which is sodium bicarbonate, to obtain G granules; then G granules are mixed with sweetener and with at least one component, which is a pharmaceutically acceptable polybasic organic acid or a partial salt thereof with alkali or alkali-earth metals, to obtain said fizzy composition. Also disclosed are: a pharmaceutical fizzy composition based on ornithine aspartate obtained using the disclosed method, and a medicinal oral form selected from a tablet, pellet or sachet containing the disclosed fizzy composition.

EFFECT: group of inventions provides improved stability of the composition with respect to chemical decomposition during its manufacturing and/or storage and, as a result, fewer impurities.

9 cl, 19 tbl, 4 dwg

Description

Scope of invention

The present invention relates to the field of pharmaceutical and nutraceutical formulations. More specifically, the present invention relates to ornithine aspartate effervescent formulations as well as methods for their manufacture.

Background of the invention

Effervescent formulations must contain significant amounts of blowing agents as well as acids in order to ensure decomposition with sufficient intensity and release enough gas to provide good taste and aroma. However, it has been found that effervescent ornithine aspartate formulations containing such blowing agents and acids are prone to chemical decomposition during manufacture and / or storage.

CN103860517A addresses this issue. The document discloses a method for preventing the formation of chemical impurities by using melt pelletizing sodium bicarbonate and polyethylene glycol (PEG 6000). The product thus obtained is mixed with granules based on ornithine aspartate previously co-granulated with tartaric acid using an anhydrous process. However, the method disclosed in CN103860517A has several disadvantages. Melt granulation is a relatively complex process that requires specialized equipment. In addition, the method enables the manufacture of formulations with low levels of impurities. Additionally, the method cannot include high levels of blowing agents and acids, thus only providing formulations with less than necessary gas bubbles.

Detailed description

Thus, the problem underlying the present invention is to provide a simple method for making chemically pure and stable ornithine aspartate formulations with high levels of gas bubbling.

This problem is solved by the present invention, which provides a method of making an effervescent ornithine aspartate composition comprising the following steps:

- granulating a mixture based on ornithine aspartate, containing ornithine aspartate and a gas-forming component, thus obtaining granules G,

- mixing the components of the final mixture containing granules G and an acid-based component, thereby obtaining an effervescent composition based on ornithine aspartate.

According to the method of the present invention, the granulation of ornithine aspartate is carried out in the presence of a blowing agent without significant amounts of acids present. However, the small amounts of acids present during this step do not have a significant negative impact. One of ordinary skill in the art, relying on impurity measurements and stability studies described herein, will be able to determine suitable maximum acid levels that may be present during this step in addition to the blowing agent. In other embodiments, granulation of a mixture based on ornithine aspartate containing ornithine aspartate and a blowing agent to obtain granules G is performed with a molar ratio of R1 = n (total amount of blowing agent material) / n (total amount of material of pharmaceutically acceptable acids, forming the acid-based component), selected from the following values: R1> 10, R1> 20, R1> 30, R1> 100. In another embodiment of the present invention, pharmaceutically acceptable acids forming the acid-based component are absent during this step. In yet another embodiment of the present invention, pharmaceutically acceptable acids are not present during this step.

Likewise, according to the process of the present invention, mixing the components of the final mixture containing granules G and an acid-based component, thereby obtaining an effervescent composition based on ornithine aspartate, is carried out without significant amounts of blowing agents added in addition to the blowing agents added with granules G ...

However, small amounts of blowing agents added in addition to the blowing agents added with the G pellets during this step do not have a significant negative effect. One of ordinary skill in the art, relying on the impurity measurements and stability studies described herein, will be able to determine suitable maximum blowing agent levels that can be added in addition to the blowing agents added with the G pellets during this step. In other embodiments, mixing the components of the final mixture containing granules G and an acid-based component to thereby obtain an effervescent composition based on ornithine aspartate is performed with a molar ratio of R2 = n (total amount of pharmaceutically acceptable acids forming the acid-based component) / n (the total amount of blowing agents added in addition to the blowing agents added with the granules G during this step) selected from the following values: R2> 10, R2> 20, R2> 30, R2> 100. In another embodiment of the present invention does not add blowing agents generating a blowing component in addition to blowing agents added with the granules G during this step. In yet another embodiment of the present invention, no blowing agents are added in addition to the blowing agents added with the granules G during this step.

L-ornithine L-aspartate is the salt of L-ornithine and L-aspartic acid. In healthy individuals who follow an adequate diet, L-ornithine and L-aspartate are synthesized de novo in sufficient quantities, but in certain conditions of the disease, as a result of tissue damage, organ failure, excessive metabolic demand, growth, pregnancy, or enzyme deficiencies the urea cycle, the addition of these amino acids was found to have beneficial effects. Both amino acids have key functions in the detoxification of ammonia and the biosynthesis of proline and polyamine. Polyamines are considered critical for DNA synthesis and cell proliferation and have been shown to stimulate liver repair. In animal models, ornithine supplementation has been shown to improve wound tear strength and collagen deposition. It has been shown in vitro, in vivo and in perfused organs that the synthesis of urea from ammonia is limited by endogenous ornithine and that the addition of ornithine can contribute significantly to the formation of urea. Low and high dose formulations of L-aspartate L-ornithine are currently on the market. Low-dose formulations are mainly used as bioactive food additives, while high-dose formulations (above 5 g) are used, for example, to reduce blood ammonia and to relieve symptoms of hepatic encephalopathy associated with liver cirrhosis. (Pol Merkur Lekarski. 2010 Jun; 28 (168): 490-5).

Effervescent formulations are designed to quickly disintegrate and quickly and simultaneously release the active ingredients they contain into an aqueous liquid. They contain a mixture of ingredients (blowing agent and acid-based component) that release carbon dioxide on contact with water. Effervescent compositions according to the present invention may further contain additional pharmaceutically acceptable ingredients such as excipients and additional excipients selected from viscosity modifiers, fillers, disintegrants, lubricants, diluents, binders, glidants, antifoam agents, wetting agents, colorants, sweeteners and flavorings.

Disintegrants promote the rapid disintegration of tablets in aqueous liquids. Disintegrants increase the surface area of the tablets in water so that the tablet in water breaks down quickly into small particles. Polymers characterized by high degradability include, but are not limited to, crosslinked sodium carboxymethyl cellulose, crosslinked hydroxypropyl cellulose, high molecular weight hydroxypropyl methyl cellulose, carboxymethylamide, copolymer of potassium methacrylate and divinylbenzene, polymethylmethacrylate cellulose polymethylthacrylate polymethylcellulose polymethylcellulose polymethylcellulose disintegrants are sodium starch glycollate, polymeric derivatives of acrylic acid, crospovidone and microcrystalline cellulose.

Fillers or diluents make the powder easier to compress and affect the hardness of the tablet after compression. They also regulate volume for activity. Such compounds include polyols, celluloses, starch and its derivatives, lactose, isomalt, maltodextrin.

Lubricants are adjuvants that reduce friction between particles within the tablet and reduce the reaction forces generated on the die wall during compression or compression. Lubricants are, for example, talc, fumarate, polyethylene glycol, benzoic acid salts such as sodium or lithium salt, L-leucine and magnesium stearate.

Flavoring agents (flavorings) determine the taste, for example, the taste of a natural fruit such as an orange, lemon, apple, strawberry, vanilla, berries, or herbs, such as peppermint, or roasted or grilled meats such as liver extracts, or yeast.

Sweeteners are, for example, saccharin, aspartame, cyclamate, sorbitol, sugar, polyols, and mixtures thereof.

Coloring agents are used to give a pleasant appearance. Such formulations are selected from any pharmaceutically or nutraceutically acceptable coloring agents approved by government regulatory authorities, for example, tartrazine (E102), quinoline yellow (E104), orange yellow (E110), and natural colors such as anthocyanins.

Examples of binders are povidone, hydroxypropyl cellulose, carbomers, acrylic polymers, gums, PVA.

Examples of glidants are colloidal anhydrous silica, talc, L-leucine, stearates.

An example of an antifoam agent is simiton.

The measure of the wetting agent is polysorbate.

Effervescent compositions of the present invention in the form of powders or granules can be prepared in numerous dosage forms, including, for example, indivisible forms such as tablets or pellets, as well as in the form of filled sachets. Tablet formulations containing the effervescent formulations of the present invention, for example, can be formed using known compression granulation techniques. In some cases, dry compaction techniques such as briquetting, compression molding, and rolling can be used.

For the purpose of administration, the effervescent compositions of the present invention or dosage forms containing the effervescent compositions of the present invention are generally dispersed in water or other aqueous liquids at room temperature and administered orally. The amount of liquid is usually the amount that can be swallowed easily. For animals, the formulations or dosage forms can be added to food or broken up in water and added to food or introduced into the oral cavity using a pipette.

The ornithine aspartate mixture granulated in the process of the present invention contains ornithine aspartate and a blowing agent. The product of this granulation are granules G. In addition to ornithine aspartate and a blowing agent, the ornithine aspartate mixture may contain one or more of the following: viscosity modifiers, fillers, disintegrants, lubricants, binders, antifoams, wetting agents, colors, sweeteners and flavors ...

According to the present invention, ornithine aspartate, a salt of ornithine and aspartic acid, is added to the ornithine aspartate mixture. In the context of the present invention, ornithine aspartate refers to L-ornithine L-aspartate, which is a salt of L-ornithine and L-aspartic acid.

The blowing component according to the present invention consists of one or more blowing means. In the presence of an acid-based component and when brought into contact with water, these blowing agents release carbon dioxide. Accordingly, the blowing agents constituting the blowing component are compounds that release carbon dioxide when brought into contact with water in the presence of the acid-based component.

In other embodiments of the present invention, the blowing agents constituting the blowing component are selected from the following: one or more carbonate salts, one or more bicarbonate salts, mixtures based on one or more carbonate salts, mixtures based on one or more bicarbonate salts, mixtures of one or more more carbonate salts with one or more bicarbonate salts.

In other embodiments of the present invention, the blowing agents constituting the blowing component are selected from the following: sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, calcium carbonate.

In other embodiments, implementation of the present invention, the blowing component consists of sodium bicarbonate.

In other embodiments, implementation of the present invention, the total amount added to the composition of blowing agents constituting a blowing component is sufficient to obtain effervescent compositions based on ornithine aspartate containing from 20 wt. % up to 40 wt. % of the gas generating component.

According to the present invention, an ornithine aspartate mixture containing ornithine aspartate and a blowing agent is granulated to thereby obtain granules G.

Granulation of the ornithine aspartate mixture can be performed using any of several methods known in the art such as aqueous granulation, non-aqueous solvent granulation, dry granulation, compression, briquetting, melt granulation, heat agglomeration, and combinations thereof. Such granulation methods are conventional in the art and are thus well known to those skilled in the art. They have also been extensively described in the literature (see, for example, Aulton's Pharmaceutics: The Design and Manufacture of Medicines, Chapter: Pharmaceutical Technology of Granule production by Michael E. Aulton, Kevin MG Taylor, Part 5, pages 472-485; Handbook of Pharmaceutical, Granulation Technology, Executive Editor James Swarbrick, PharmaceuTech Inc. Pinehurst, North Carolina. 2005 by Taylor & Francis Group, LLC. Chapter, Theory Of granulation: An Engineering prospective, pages 7-60).

In other embodiments of the present invention, the granulation conditions used to granulate the ornithine aspartate mixture are selected from the following: wet granulation, dry granulation, melt granulation.

Given the fact that melt granulation is a relatively complex process requiring specialized equipment, whereas the process of the present invention does not need to apply melt granulation conditions, in a particular embodiment of the present invention, the process does not use the granulation conditions from melt.

According to the present invention, the components of the final mixture containing granules G and an acid based component are mixed to thereby obtain an effervescent ornithine aspartate composition.

In addition to granules G and an acid-based component, the final blend according to the present invention may contain one or more of the following: viscosity modifiers, fillers, disintegrants, lubricants, diluents, binders, glidants, antifoams, wetting agents, colors, sweeteners and flavors.

Blending of the final blend can be accomplished using any of several methods known in the art such as agitation, high shear blending, geometric blending, inversion blending, co-milling, etc. Such blending methods are common in the art. and thus are well known to the person skilled in the art. They have also been extensively described in the literature (see, for example, Powder Technology, Handbook, Marcel Dekker, New York, 1997, pages 43-56; Pharmaceutical Blending and Mixing, 1st edition, edited by PJ Cullen, Rodolfo Roma Ãach, Nicolas Abatzaglou, Chris D. Rielly. Willey Publication. Chapter 6, Continuous Powder Mixing. Pp. 102-484).

In other embodiments of the present invention, the mixing conditions used to mix the final mixture are selected from the following: mixing, high shear mixing, geometric mixing.

The acid-based component of the present invention consists of one or more organic or inorganic pharmaceutically acceptable acids. In the presence of an acid-based component and when brought into contact with water, the blowing agents release carbon dioxide. Accordingly, the pharmaceutically acceptable acids constituting the acid-based component are compounds that cause the release of carbon dioxide upon contact with water in the presence of a blowing agent.

In other embodiments of the present invention, the pharmaceutically acceptable acids constituting the acid-based component are selected from the following acids, as well as partial salts of the following acids with alkali or alkaline earth metals in the case of polybasic acids: citric acid, tartaric acid, malic acid, adipic acid, succinic acid, fumaric acid, ascorbic acid, maleic acid, mixtures thereof.

In other embodiments, implementation of the present invention, the acid component consists of citric acid.

According to the present invention, the pharmaceutically acceptable acids constituting the acid-based component are added in a total molar excess to the blowing components constituting the blowing component. Typically, the pharmaceutically acceptable acids constituting the acid-based component and the blowing agents constituting the blowing component are added to the composition in an amount to provide effervescent compositions with a molar ratio of acid-based component to blowing component in the range of 7: 1 to 1.1. : 1.

An advantage of the method of the present invention lies in the fact that it can be carried out at high humidity levels, including humidity levels of no more than 50% relative humidity.

The present invention further provides ornithine aspartate effervescent formulations obtainable by the method of the present invention.

In addition to ornithine aspartate, blowing agent and acid-based component, the effervescent compositions of the present invention may further comprise one or more auxiliary substances selected from the following: viscosity modifiers, fillers, disintegrants, lubricants, diluents, binders, glidants, antifoams agents, wetting agents, colorants, sweeteners, flavors.

In a specific embodiment of the present invention, the effervescent compositions of the present invention contain one or more additional pharmaceutically acceptable ingredients selected from: fillers, lubricants, diluents, binders, glidants, colorants, sweeteners, flavorings.

Typically, the effervescent formulations of the present invention contain ornithine aspartate, a blowing agent, an acid-based component and additional pharmaceutically acceptable ingredients at the following percentages (for each particular formulation, percentages should be chosen to add up to 100%):

ornithine aspartate: 10% -60%;

gas-forming component: 10% -40%;

acid based component: 15% -50%;

fillers / thinners: 0% -25%;

lubricants / glidants: 0% -15%;

binders: 0% -10%;

sweeteners: 0% -10%;

fragrances: 0% -2%.

In a specific embodiment of the present invention, the effervescent compositions of the present invention comprise ornithine aspartate, a blowing agent and an acid-based component, and the following pharmaceutically acceptable ingredients: fillers, lubricants, diluents, binders, glidants, colorants, sweeteners and flavors ...

In another aspect, the present invention provides a method of making stable effervescent ornithine aspartate formulations containing large amounts of blowing agents. Formulations containing large quantities of blowing agents are necessary for a number of applications because they are capable of imparting a pleasant taste to beverages derived from them due to the saturation of the liquid with carbon dioxide and the release of carbon dioxide in gaseous form. One reason for this effect is that dissolved carbon dioxide produces flavor by interacting directly with the sour taste buds. In addition, the released carbon dioxide in gaseous form contributes to the improvement of flavor and thus also indirectly influences the taste through the olfactory perception. Accordingly, the amount of carbon dioxide that can be produced by the effervescent composition is an important factor and in the context of the present invention it refers to the gas-generating capacity of the effervescent composition. In order to impart favorable taste properties to the drink obtained from them, it is necessary to use effervescent dosage forms characterized by a sufficient ability to form a gas to saturate the drink with carbon dioxide. Considering the fact that the typical volume of a beverage made from an effervescent composition is approximately 100 ml and, in addition, that 100 ml of water can dissolve approximately 150 mg of carbon dioxide at room temperature (25 ° C), the ability to generate gas in an amount of 150 mg carbon dioxide is usually sufficient to provide the appropriate palatability.

Therefore, in one embodiment, the method of the present invention provides ornithine aspartate effervescent formulations having the ability to generate gas in an amount greater than 150 mg carbon dioxide per gram of ornithine aspartate.

Accordingly, in one embodiment, the present invention further provides ornithine aspartate effervescent formulations obtainable by the process of the present invention having the ability to generate gas in an amount greater than 150 mg of carbon dioxide per gram of ornithine aspartate.

As indicated above, the effervescent compositions of the present invention in the form of powders or granules can be prepared in numerous dosage forms, including, for example, indivisible forms such as tablets or pellets, as well as in the form of filled sachets. Accordingly, in another embodiment, the present invention provides tablets, pellets or sachets containing the effervescent ornithine aspartate formulations of the present invention.

Description of graphic materials

FIG. 1. Diagram of the manufacturing method

FIG. 2. Characteristics with respect to gas bubbling / CO ₂ generation for sample GI in water (100 ml) at 25 ° C

FIG. 3. Characteristics with respect to gas bubbling / CO ₂ generation for HI, JI, NI OC, PI, QC samples in water (100 ml) at 25 ° C

FIG. 4. Characteristics with respect to gas bubbling / CO ₂ generation for sample VI in water (100 ml) at 25 ° C

Examples of

(1) Analytical method

The following section describes the analytical methods used to analyze samples A-V below.

Method for analyzing the amount of impurity

Chromatography conditions

Column: Waters Spherisorb Amino 5 micron (250 x 4.6) mm;

Mobile phase: buffer: acetonitrile (27.5: 72.5);

buffer: 0.05 M KH ₂ PO ₄ ;

wavelength: 210 nm;

pace. columns: 25 ° C;

volume of injected sample: 100 μl;

flow rate: 1.0 ml / minute

run time: 120 minutes;

pace. Sample: environment.

The solvents used met the HPLC purity requirements.

Diluent: mobile phase.

Preparation of a standard solution

Impurity solution for L-ornithine lactam ((3S) -3-aminopiperidin-2-one * Hcl). 5 mg of impurity was weighed and transferred to a 100 ml volumetric flask. Added 30 ml of water and sonicated with dissolution. Diluted to the mark with water. (Example: concentration is 50 ppm).

Fumaric acid solution. Weighed 20 mg of fumaric acid and transferred to a 1000 ml volumetric flask. Added 300 ml of water and sonicated with dissolution. Diluted to the mark with water. (Example: concentration is 20 ppm).

Malic acid solution. Weighed 150 mg of malic acid and transferred to a 100 ml volumetric flask. Added 30 ml of water and sonicated with dissolution. Diluted to the mark with water. (Example: concentration - 1500 ppm).

L-arginine solution. 50 mg of L-arginine was weighed and transferred to a 100 ml volumetric flask. Added 30 ml of water and sonicated with dissolution. Diluted to the mark with water. (Example: concentration is 500 ppm).

Preparation of a solution to determine the suitability of the system

Weighed 130 mg of L-ornithine API L-aspartate and transferred to a 50 ml volumetric flask. 2 ml of each of the stock solutions of impurities was transferred to a flask and diluted to the mark with diluent. (Example: concentration values: lactam 2 ppm, fumaric acid 0.8 ppm, malic acid 60 ppm, L-arginine 20 ppm, L-ornithine L-aspartate 2600 ppm).

Getting a sample

For sachets containing effervescent granules, the entire contents of five sachets were discarded and weighed to obtain the average weight of the sachet. For effervescent tablets, five tablets were weighed to obtain an average tablet weight, and then crushed into powder. An amount of the effervescent composition to be analyzed, equivalent to 1000 mg of L-aspartate L-ornithine, was weighed and transferred to a 100 ml volumetric flask. Added 30 ml of water and allowed the evolution of gas bubbles to complete. Subjected to dissolution sonication and diluted to the mark with water. This solution was a stock solution containing approximately 10,000 ppm L-aspartate L-ornithine. In addition, 3 ml of the stock solution was transferred into a 10 ml volumetric flask and diluted to the mark with the mobile phase (for example, the concentration of L-aspartate L-ornithine is 3000 ppm). The solution was filtered through a 0.45 micron nylon filter. The first few ml of the filtrate was removed. This solution was a sample solution for introduction into the chromatographic system.

Getting a placebo

A placebo equivalent to 1000 mg of L-aspartate L-ornithine was weighed (amount of placebo = average weight of the sachet or tablet - the content of L-aspartate L-ornithine in each sachet or tablet (namely 1000 mg)) and transferred to a 100 ml volumetric flask. Added 30 ml of water and allowed the evolution of gas bubbles to complete. Subjected to dissolution sonication and diluted to the mark with water. This solution was the stock solution. In addition, 3 ml of the stock solution was transferred into a 10 ml volumetric flask and diluted to the mark with the mobile phase. The solution was filtered through a 0.45 micron nylon filter. The first few ml of the filtrate was removed. This solution was a placebo solution for injection into the chromatographic system.

Procedure

The chromatograph was injected with 100 μl of each diluent, system suitability solution, fumaric acid solution (0.8 ppm) and placebo solution, and chromatograms were recorded. Ensure that the system suitability parameters are met and that there is no effect of blank and placebo chromatograms at retention times of major and impurity peaks.

The sequence of samples for six batches, as a rule, one after another was as shown below. The same sequence was applied for six more games.

System suitability

The following system suitability criteria were measured by injecting a solution to determine system suitability:

the number of theoretical plates for the peak of L-aspartic acid is not less than 2000;

% RSD for the area of impurity peaks not more than 3%.

Payment

% of a single known impurity in the sample

,

,

Where:

A sample: the area of the impurity peak obtained from the measurement of the sample solution;

A std .: mean peak area of impurity obtained from a series of measurements of solutions to determine system suitability;

Standard weight: weight of standard impurity solution in mg;

Sample weight: sample weight in mg;

D Outcome: the final volume of dilution of the stock solution of the impurity in ml;

LC: content of L-aspartate L-ornithine in each sachet or tablet in mg;

Average: Average weight of a sachet or tablet in mg.

Note: The calculation of the amount of known impurities was performed by using the areas of individual impurity peaks observed in the solution to determine the suitability of the system.

% of unknown impurity in the sample

,

,

Where:

A sample: the area of the impurity peak to obtain the sample;

A total: total area in the chromatogram of the sample;

A placebo: placebo peak area on the chromatogram of the sample;

A blank: the area of the peaks of the blank in the sample chromatogram.

% of the total amount of impurities in the sample

% of individual known impurity +% of individual unknown impurity

Total impurity in the sample (in ppm)

% of total impurity x 10000

Analytical method for characterizing the evolution of gas bubbles

The samples were placed in a glass beaker containing 100 ml of demineralized water at a temperature of 25 ° C. The change in the total weight of the contents was noted using a suitable digital scale over a period of 10 minutes. The total time required for visual cessation of gas bubbles was also noted. The amount of CO ₂ dissolved in water was calculated arithmetically by subtracting the amount of gas evolved in 10 minutes from the theoretical value for the gas forming ability.

(2) Detailed composition description

Ingredient List

The following is a list of excipients, manufacturers and descriptions used in the examples below (USP = US Pharmacopoeia, BP = UK Pharmacopoeia).

Table 1. List of used ingredients

A schematic of the manufacturing method is shown in FIG. 1.

Oral L-Aspartate L-Ornithine Formulations

The subscripts indicate the type of example: C = comparative example; I = example according to the present invention.

Table 2. Compositions of examples A-F

Table 3. Composition of example GI

Detailed description of the method of obtaining samples

Examples BC and CC: L-ornithine L-aspartate was granulated using purified water, dried and sized with either citric acid (Example B) or sodium bicarbonate (Example C) mixed.

Example DC: L-ornithine L-aspartate was granulated with citric acid and sodium bicarbonate using purified water, dried and sized.

Examples EC and FI: L-ornithine L-aspartate was granulated using purified water with either citric acid (Example E) or sodium bicarbonate (Example F), dried and sized. These granules were further mixed with sodium bicarbonate (Example E) or citric acid (Example F).

Example GI: L-ornithine L-aspartate, PVP K25 povidone, color and sodium bicarbonate were accurately weighed, mixed and granulated with water. The dried granules (part A) were sized and mixed with aspartame, orange flavor, isomalt, and anhydrous citric acid (part B).

The resulting mixed granules were finally packed in HDPE bottles for stability studies carried out over a period of 12 days at 40 ° C / 75% RH (relative humidity).

Table 4. Impurity results. Influence of the method of incorporating acidifying agent and blowing agent on the stability of L-aspartate L-ornithine granules (* -> Total impurities expressed in parts per million (PPM))

Notes on impurities in Examples AC-GI: The amount of impurities generated in Examples of the present invention (FI-GI) was lower than in Comparative Examples (BC-EC).

Sample GI was analyzed for bubble / CO ₂ performance in water (100 ml) at 25 ^° C (see FIG. 2).

Table 5. Characteristics with respect to gas bubbling / CO ₂ generation for sample GI

Given that the solubility of carbon dioxide in water at 25 ^° C is approximately 1.45 g / L (as stated on Wikipedia), Sample G could oversaturate the drink with carbon dioxide providing sufficient carbonation to impart good flavor.

Based on the above data, it was planned to conduct additional experiments to further investigate the effect of the method and the amount of acidifying substance in the compositions by applying the above methods.

Table 6. Examples of HI, II and JI (according to the present invention)

Detailed description of the method for obtaining examples HI, II and JI

Part A. L-ornithine L-aspartate, PVP K25 povidone, colorant and sodium bicarbonate were accurately weighed, mixed and granulated with water in a high speed mixer granulator. The granules were dried in a fluidized bed unit to LOD <1%. The dried granules were sized to form granules that pass through an ASTM # 25 sieve.

Part B. Aspartame, flavor, isomalt and anhydrous citric acid were passed through an ASTM # 25 sieve.

Parts A and B were mixed together for 5 minutes.

Table 7. Composition of examples KC, LC and MC (comparative)

Detailed description of the method for obtaining examples of KC, LC and MC

Part A. L-ornithine L-aspartate, PVP K25 povidone, color and citric acid were accurately weighed, mixed and granulated with water in a high speed mixer granulator. The granules were dried in a fluidized bed unit to LOD <1%. The dried granules were sized to form granules that pass through an ASTM # 25 sieve.

Part B. Aspartame, flavor, isomalt and sodium bicarbonate were passed through an ASTM # 25 sieve.

Parts A and B were mixed together for 5 minutes.

These samples (H-M) were tested for the formation of impurities during storage. The results are shown in Table 8 below.

Table 8. Impurity data for samples H-M

Notes on impurities in Examples HI-MC: The amount of impurities formed in Examples of the present invention (HI-JI) was significantly lower than in Comparative Examples (KC-MC). This indicates the importance of the method of adding acidic and blowing components.

Based on the above results, additional experiments (NI, OC and PI) were planned to evaluate the bubbling performance using compositions with different gas generating characteristics. Additionally, example Q C was planned to study properties compared to the prior art (CN103860517).

Table 9. Examples of NI, OC and PI

Detailed description of the method for obtaining examples of NI, OC, PI

Part A. L-ornithine L-aspartate, PVP K25 povidone, colorant and sodium bicarbonate were accurately weighed, mixed and granulated with water in a high speed mixer granulator. The granules were dried in a fluidized bed unit to LOD <1%. The dried granules were sized to form granules that pass through an ASTM # 25 sieve.

Part B. Aspartame, flavor, isomalt and anhydrous citric acid were passed through an ASTM # 25 sieve.

Parts A and B were mixed together for 5 minutes.

In the case of example N; part A, part B, PEG 6000 and L-leucine were mixed together and compressed into tablets using a 25 mm tablet press.

Table 10. QC example (according to CN103860517)

Detailed description of the way to get the QC example

Part A. L-ornithine L-aspartate and tartaric acid were mixed together. Kollidone VA 64 was dissolved in ethanol to give an 8% solution. This solution was used to granulate the powder mixture and dried. The dried granules were sized to form granules that pass through an ASTM # 25 sieve.

Part B. PEG 6000 was mixed with sodium bicarbonate and melt granulated at 60 degrees Celsius in a water bath. Cooled and milled to pass through # 25 sieve ASTM.

Parts A and B were mixed together for 5 minutes.

Samples HI, JI, NI OC, PI, QC were analyzed for performance in terms of bubbling / CO ₂ generation in water (100 ml) at 25 ° C (see FIG. 3).

Table 11. Characteristics with respect to gas bubbling / formation of CO ₂ for samples in water (100 ml) at 25 ^o C

Notes on the bubbling characteristics of Examples HI, JI and NI-QC: Given that the solubility of carbon dioxide in water at 25 ^° C is approximately 1.45 g / L (as listed on Wikipedia), all samples with the exception of the comparative examples (OC and QC), the beverage could be oversaturated with carbon dioxide to provide sufficient carbonation to impart good taste.

The impurity formation results for Examples HI, NI and QC are shown in the table below.

Table 12. Impurity data for samples HI, NI and QC

Notes on impurities in Examples HI, NI and QC: The amount of impurities formed in the examples of the present invention (HI and NI) was significantly lower than in the comparative examples from the prior art (QC). This indicates the importance of the method of adding acidic and blowing components.

Further examples were examined to confirm the effect of a change in acid type on the impurity formation properties of the present invention.

Table 13. Example RI (substitution of citric acid for tartaric acid) - positive example

A detailed description of the method for obtaining an example of RI

Part A. L-ornithine L-aspartate, PVP K25 povidone, colorant and sodium bicarbonate were accurately weighed, mixed and granulated with water in a high speed mixer granulator. The granules were dried in a fluidized bed unit to LOD <1%. The dried granules were sized to form granules that pass through an ASTM # 25 sieve.

Part B. Aspartame, flavor, isomalt and tartaric acid were passed through an ASTM # 25 sieve.

Parts A and B were mixed together for 5 minutes.

Table 14 Composition of Example SC (Comparative to Example RI)

Detailed description of the method for obtaining an example SC

Part A. L-ornithine L-aspartate, PVP K25 povidone, dye and tartaric acid were accurately weighed, mixed and granulated with water in a high speed mixer granulator. The granules were dried in a fluidized bed unit to LOD <1%. The dried granules were sized to form granules that pass through an ASTM # 25 sieve.

Part B. Aspartame, flavor, isomalt and sodium bicarbonate were passed through an ASTM # 25 sieve.

Parts A and B were mixed together for 5 minutes.

Table 15 Impurity data for RI and SC samples

Notes on impurities in examples RI and SC: The amount of impurities generated in the example of the present invention (RI) was significantly lower than in comparative examples (SC). Thus, as expected, despite the change in the acid type, the impurity formation properties of the composition remained unchanged.

In order to study the applicability of the present invention to the type of granulation techniques, additional experiments (TI and UI) were planned. Investigated the effect of melt granulation and dry granulation.

Table 16. Examples of TI and UI (of the present invention, demonstrating dry granulation and melt granulation techniques)

Detailed description of the method of obtaining

Dry granulation (example TI)

Part A. L-ornithine L-aspartate, PVP K25 povidone, dye and sodium bicarbonate were accurately weighed, passed through an ASTM # 40 sieve and mixed for 5 minutes. The resulting mixture was compressed to obtain compressed products. The compressed products were ground and sized through an ASTM # 25 sieve.

Part B. Aspartame, flavor, isomalt and anhydrous citric acid were passed through an ASTM # 25 sieve.

Parts A and B were mixed together for 5 minutes.

Melt Granulation (UI Example)

Part A. L-ornithine L-aspartate, PEG 6000, dye and sodium bicarbonate were accurately weighed and passed through an ASTM # 40 sieve and mixed. The resulting blended mixture was transferred to a glass beaker and heated at 65 ^° C on a hot plate and blended to ensure a uniform mixture. Upon completion of the PEG 6000 melting, the molten mass was removed, cooled and sieved through an ASTM # 25 sieve.

Part B. Aspartame, flavor, isomalt and anhydrous citric acid were passed through an ASTM # 25 sieve.

Parts A and B were mixed together for 5 minutes.

Samples TI and UI were tested for impurity formation during storage. The results are shown in the table below.

Table 17. Impurity data for TI and UI samples

Notes on impurities in Examples TI and UI: The amount of impurities generated in both examples of the present invention (TI and UI) did not increase significantly, and the properties were similar to those of other examples of the present invention mentioned earlier. Thus, despite the changes in the type of granulation technique, the properties of the composition in relation to the formation of impurities remained unchanged.

Another experiment (Sample VI), described below, was planned using ascorbic acid as the acidic component and elderberry extract as color and flavor.

Table 18. Composition of Example VI

Detailed description of the method for obtaining example V

Part A. L-ornithine L-aspartate and sodium bicarbonate were accurately weighed, mixed and granulated with water in a high speed mixer granulator. The granules were dried in a fluidized bed unit to LOD <1%. The dried granules were sized to form granules that pass through an ASTM # 25 sieve.

Part B. Aspartame, elderberry extract, isomalt and ascorbic acid were passed through an ASTM # 30 sieve.

Parts A and B were mixed together for 5 minutes.

Sample VI was analyzed for bubble / CO ₂ performance in water (100 ml) at 25 ^° C (see FIG. 4).

Table 19. Characteristics with respect to gas bubbling / CO ₂ formation for sample V in water (100 ml) at 25 ^o C

Notes on the bubbling performance of Example VI: As observed with the other examples of the present invention, Example VI had acceptable bubbling performance. No significant effect of changing the acidic component, colorant, or flavor was observed.

Claims (11)

1. A method of manufacturing an effervescent composition based on ornithine aspartate, including the following stages: granulating a mixture based on ornithine aspartate containing ornithine aspartate and a gas-forming component, sodium bicarbonate, thus obtaining granules G, - mixing granules G with a sweetener and with at least one component, which is a pharmaceutically acceptable polybasic organic acid or partial salt thereof with alkali or alkaline earth metals, thereby obtaining an effervescent composition based on ornithine aspartate. 2. The method according to claim 1, wherein the granulation of the mixture based on ornithine aspartate is carried out under granulation conditions selected from the following: wet granulation, dry granulation. 3. A method according to any one of claims 1 to 2, wherein the total content of the blowing agents added to the composition, constituting the blowing component, is from 10 to 40 wt.%. 4. A method according to any one of claims 1 to 3, wherein the pharmaceutically acceptable polybasic organic acid is selected from citric acid, tartaric acid, malic acid, adipic acid, succinic acid, fumaric acid, ascorbic acid, maleic acid. 5. The method of claim 4, wherein the pharmaceutically acceptable polybasic organic acid is selected from citric acid. 6. A pharmaceutical effervescent formulation based on ornithine aspartate obtained by a method according to any one of claims 1 to 5. 7. An effervescent composition according to claim 6, containing one or more auxiliary substances selected from the following: viscosity modifiers, fillers, disintegrants, lubricants, diluents, binders, glidants, antifoams, wetting agents, colorants, flavors. 8. An effervescent composition according to any one of claims 6 to 7, characterized by the ability to generate gas in an amount exceeding 150 mg of carbon dioxide per gram of ornithine aspartate. 9. An oral dosage form selected from a tablet, pellet or sachet containing an effervescent composition according to any one of claims 6 to 8.

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